Process for the manufacture of arylsulfonyl chloride

ABSTRACT

A process is described for the manufacture of a pyridinesulfonyl chloride or a benzenesulfonyl chloride in which the benzene ring bears one or more electron-withdrawing groups, the process comprising reacting a diazonium salt of an aminopyridine or aminobenzene in which the benzene ring bears one or more electron withdrawing groups with a mixture of thionyl chloride in water, in the presence of an electron transfer catalyst.

This invention concerns a novel chemical process and, more particularly,it concerns a novel chemical process for the manufacture ofpyridinesulfonyl chlorides and certain benzenesulfonyl chlorides.

Pyridinesulfonyl chlorides and benzenesulfonyl chlorides are useful inthe manufacture of compounds having a variety of uses, such as in themanufacture of pharmaceuticals or herbicides. For example2-chloropyridine-3-sulfonyl chloride is particularly useful in theproduction of the endothelin antagonists described in InternationalPatent Application, Publication No. WO 96/40681.

A number of methods are known for preparing pyridinesulfonyl chlorides(such as 2-chloropyridine-3-sulfonyl chloride) and benzenesulfonylchlorides. One such method involves reaction of the diazonium salt ofthe corresponding aminopyridine (such as 3-amino-2-chloropyridine) oraromatic amine with sulfur dioxide in the presence of acetic acid andusing CuCl or CuCl₂ as catalyst, followed by isolation of the product bysolvent extraction. Such a method is disclosed in WO 96/40681 andEuropean Patent Application, Publication Nos. 733629 and 618209. Similarmethods are disclosed in Synthesis, (1969), 6, No. 1, pages 3-10 andRec. Trav. Chim., (1965), 84, pages 24-29.

A disadvantage with carrying out this process on a large scale is thedifficulty associated with the isolation of the product free ofimpurities at the end of the reaction. In particular it is oftendifficult on a large scale to obtain the product free of acetic acid orprevent hydrolysis of the product to the corresponding sulfonic acid onwork-up. A further disadvantage of carrying out this process on a largescale is the use of the gaseous reagent, sulfur dioxide. Thesedisadvantages make this process unattractive for operation on acommercial scale.

Surprisingly, a process has now been discovered for the manufacture ofpyridine sulfonyl chlorides and certain benzenesulfonyl chlorides whichavoids the use of both acetic acid and sulfur dioxide gas and whichovercomes the isolation problems encountered with the known process.

According to the invention there is provided a process for themanufacture of a pyridinesulfonyl chloride or a benzenesulfonyl chloridein which the benzene ring bears one or more electron-withdrawing groupswhich comprises reaction of the diazonium salt of an aminopyridine oraminobenzene in which the benzene ring bears one or moreelectron-withdrawing groups with a mixture of thionyl chloride in water,in the presence of an electron transfer catalyst.

A particular aspect of the present invention is a process for themanufacture of a pyridinesulfonyl chloride which comprises reaction ofthe diazonium salt of an aminopyridine with a mixture of thionylchloride in water, in the presence of an electron transfer catalyst.

A further particular aspect of the present invention is a process forthe manufacture of a benzenesulfonyl chloride in which the benzene ringbears one or more electron-withdrawing groups (more particularly one ortwo electron-withdrawing groups) which comprises reaction of thediazonium salt of an aminobenzene, in which the benzene ring bears oneor more electron-withdrawing groups, with a mixture of thionyl chloridein water, in the presence of an electron transfer catalyst.

It will be appreciated that, where a pyridinesulfonyl chloride or anaminopyridine is referred to, the pyridine ring may be unsubstituted ormay bear one or more substituents. A particular substituent includes,for example, an electron-withdrawing substituent.

A preferred electron transfer catalyst includes, for example, cupricchloride (CuCl₂) and cuprous chloride (CuCl), especially the latter.Preferably 0.012 to 0.05 equivalents of catalyst (per equivalent ofamino compound) are used.

It is well known that functional groups or substituents can beclassified as electron-withdrawing (−I) or electron-donating (+I) groupsrelative to hydrogen, as disclosed by J. March in Advanced OrganicChemistry, Fourth Edition, Wiley & Sons. Typical electron-withdrawinggroups are referred to or listed in the above publication and disclosureof these are incorporated herein by reference. Particularelectron-withdrawing groups include, for example, chloro, bromo, cyano,nitro and carboxy.

The preparation of the diazonium salt of a primary aromatic orheteroaromatic amine is well known in the art of organic chemistry, byreaction of the amine with nitrous acid. For the process of the presentinvention it is convenient to generate the nitrous acid in situ by theconventional method of reacting an alkali metal nitrite, especiallysodium nitrite, with a mineral acid, especially hydrochloric acid, inthe presence of the amino compound. The diazotisation reaction isgenerally carried out at a temperature in the range of about +5 to −10°C., and preferably at about +1 to −4° C. It is preferred to use about 1to 1.2 equivalents of alkali metal nitrite and 3 to 20 (more preferably11 to 13) equivalents of concentrated (approximately 36%) hydrochloricacid (per equivalent of amino compound). When the starting material isan aminobenzene bearing one or more electron-withdrawing groups, it ispreferred that the amine is added to the mineral acid and this mixtureheated at 30 to 50° C. for 10 to 60 minutes (to ensure complete saltformation) prior to cooling and addition of the aqueous sodium nitritesolution. The water charge to dissolve the sodium nitrite is generallybetween 1 to 5 volumes based on the input weight of amino compound,although solid nitrite may alternatively be added portionwise to themixture of the amine in hydrochloric acid. It is preferable to use thediazonium salt solution or slurry so generated immediately afterpreparation because of the instability of the diazoniun salt,maintaining the temperature of the solution or slurry at about +1 to −4°C. during the addition.

It is preferred that 2 to 12 equivalents of thionyl chloride are usedper equivalent of amino compound, and especially 4 to 5 equivalents.

It is preferred that the water charge for thionyl chloride dissolutionis between 5 to 30 volumes (and more preferably 10 to 20 volumes) ofwater, based on the input weight of amino compound.

It is preferred that the thionyl chloride and water mixture ismaintained at 18-25° C., and conveniently at about ambient temperature,for 1 to 48 hours, and conveniently 15 to 20 hours (for exampleovernight), prior to reaction with the diazonium salt.

It is preferred that the solution of the diazonium salt is added over asshort a time as possible consistent with maintaining the exothermicreaction at a temperature between −10 and +5° C., and preferably between−4 and +1° C. After addition it is preferred that the reaction ismaintained at about this temperature for 15 to 90 minutes.

The product may be isolated by extraction into a suitable solvent, suchas a hydrocarbon, chlorinated hydrocarbon or ether solvent immisciblewith water, such as dichloromethane, diethyl ether or preferablytoluene. The absence of acetic acid in the reaction mixture means thatdifficulties associated with the presence of acetic acid in the solventextract (and its subsequent removal) are avoided. The advantage of usingtoluene as the extraction solvent is that the extract can be washed withwater and any residual traces of water and entrained HCl removed byazeotropic distillation to give the product as a solution in toluene,which can then be used directly in a subsequent reaction or the toluenecan be removed under vacuum to give the product which may berecrystallised in high purity, for example from a non-polar solvent suchas n-hexane, isohexane or cyclohexane.

Alternatively, where the product is a solid sulfonyl chloride, it mayprecipitate from the reaction mixture and be collected by filtrationinstead of by solvent extraction.

The process of the invention is particularly suitable for preparing2-halogenopyridine-3-sulfonyl chlorides such as2-chloropyridine-3-sulfonyl chloride.

A further surprising advantage found with the process of the presentinvention when it is used to prepare 2-chloro-3-pyridinesulfonylchloride is that the product precipitates from the reaction mixture inhigh purity as the free base and can be collected by filtration. It isbelieved that all previously known methods for preparing2-chloro-3-pyridinesulfonyl chloride from the diazonium salt of3-amino-2-chloropyridine require isolation by extraction, because of theuse of acetic acid in the reaction.

The present invention also provides a process for preparing certainendothelin antagonists disclosed in WO 96/40681, which is incorporatedherein by reference.

Thus, according to another aspect, the invention provides a process forthe preparation of a compound of the formula I

or a pharmaceutically acceptable salt thereof, wherein R is (1-4C)alkylor carboxy(1-4C)alkyl which comprises the steps of:

(a) reaction of the diazonium salt of 3-amino-2-chloropyridine with amixture of thionyl chloride in water, in the presence of an electrontransfer catalyst, to give 2-chloropyridine-3-sulfonyl chloride;

(b) reaction of 2-chloropyridine-3-sulfonyl chloride with isobutylN-(3-methoxy-5-methylpyrazin-2-yl)carbamate in the presence of an alkalimetal hydride in an inert solvent to give2-chloro-N-isobutoxycarbonyl-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulfonamide;

(c) reaction of2-chloro-N-isobutoxycarbonyl-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulfonamidewith a boronic acid of the formula II,

 (or an anhydride or ester thereof) in the presence of a base and in thepresence of a palladium (0), palladium (II), nickel (0) or nickel (II)catalyst in a suitable solvent; followed by removal of theisobutoxycarbonyl protecting group;

whereafter, when a pharmaceutically acceptable salt of a compound offormula I is required, it is obtained by reaction with the appropriateacid or base affording a physiologically-acceptable ion, or by any otherconventional salt formation procedure.

Step (a) may be carried out as described above.

Step (b) may be carried out, for example, using an alkali metal hydride(such as sodium or potassium hydride) in a inert solvent such as DMF,pyridine or toluene. The reaction is carried out at a temperature in therange of, for example, 0° C. to 70° C. A typical example of step (b) isdescribed in Example 1 (ii) of WO 96/40681. The compound isobutylN-(3-methoxy-5-methylpyrazin-2-yl)carbamate may, for example, beobtained as described in Example 1 of WO 96/40681.

In Step (c), suitable catalysts include, for example,tetrakis(triphenylphosphine)nickel(0),bis(triphenylphosphine)nickel(II)chloride, nickel(II)chloride,bis(triphenylphosphine)palladium(II)chloride, palladium(II)chloride andtetrakis(triphenylphosphine)palladium(0), of which the latter is apreferred catalyst. A suitable base for use in the reaction is, forexample, an alkali metal alkoxide (such as sodium methoxide or sodiumethoxide), an alkali metal hydroxide (such as sodium or potassiumhydroxide), an alkali metal carbonate (such as sodium or potassiumcarbonate), or an organic base (such as tri(1-6C)alkylamine, forexample, triethylamine). Of these, sodium carbonate is a preferred base.The coupling is generally performed in the presence of a suitablesolvent or diluent, for example, a hydrocarbon (such as toluene orxylene), an ether (such as dioxan or tetrahydrofuran), an (1-4C)alcohol(such as methanol, ethanol or butanol), water or mixtures thereof (forexample, a mixture of toluene, ethanol and water, which is preferred).The reaction is generally performed at a temperature in the range, forexample, 50-150° C., and conveniently at or about the reflux temperatureof the solvent or mixture of solvents used. Examples of step (c) aredescribed in WO 96/40681, in Examples 1(iii), 11(ii), 12(ii), 13(ii),14(ii), 58(vii) and 64(iv) thereof. Alternatively, the coupling may becarried out using a source of fluoride ion under aqueous conditions, forexample using potassium fluoride in a mixture of toluene and water underreflux, by analogy with Example 30(ii) of WO 96/40681.

Removal of the isobutoxycarbonyl protecting group may be carried outafter isolation of the protected product under basic conditions, such asby employing sodium hydroxide or alkoxide (e.g. methoxide) in a suitablesolvent such as methanol (for example as described in Examples 1, 11,12, 13, 14, 58 and 64 of WO 96/40681). Alternatively, theisobutoxycarbonyl group may be removed by in situ hydrolysis, forexample, by addition of further water to the reaction mixture.

The process is particularly suitable for preparing the compound offormula I in which R is 2-carboxy-2-methylpropyl.

According to another aspect, the invention provides a process for thepreparation of a compound of the formula I wherein R is1,3,4-oxadiazol-2-yl which comprises steps (a) and (b) above followed bythe additional steps of:

(i) reaction of2-chloro-N-isobutoxycarbonyl-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulfonamidewith 4-methoxycarbonylphenylboronic acid (or an anhydride or esterthereof) in the presence of a source of fluoride ion and under aqueousconditions to giveN-(isobutoxycarbonyl)-2-(4-methoxycarbonylphenyl)-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulfonamide;

(ii) removal of the isobutoxycarbonyl protecting group;

(iii) conversion of the methyl ester (—CO.OCH₃) group to thecorresponding hydrazide (—CONHNH₂); and

(iv) conversion of the hydrazide group to a 1,3,4-oxadiazol-2-yl moiety;

whereafter, when a pharmaceutically acceptable salt of a compound offormula I is required, it is obtained by reaction with the appropriateacid or base affording a physiologically-acceptable ion, or by any otherconventional salt formation procedure.

Step (i) may be carried out, for example, by using potassium fluoride asthe source of fluoride ion and employing as solvent a mixture of xylene,methanol and water, or a mixture of toluene and water. The reaction isconveniently carried out at the reflux temperature of the solventmixture employed. A typical example of step (i) is exemplified inExample 30 (ii) of WO 96/40681.

Step (ii) may be carried out, for example, under basic conditions, suchas by using a mixture of methanol and aqueous ammonia, or sodiummethoxide in methanol. It may be carried out after first isolating theproduct obtained in (i) (as illustrated in Example 32 of WO 96/40681) orthe reaction mixture from (i) may be diluted with water and the organicphase separated, filtered and the filtrate diluted with methanol,followed by the addition of aqueous ammonia. The product may then beisolated by addition of water and precipitation by addition of aceticacid.

Step (iii) may be carried out, for example, by reacting the product ofstep (ii) with hydrazine hydrate in a suitable solvent, such asdichloromethane and water. The hydrazide precipitates as the hydrazinesalt and may be converted to the free hydrazide by addition of aqueoushydrochloric acid and isolated by filtration.

Step (iv) may be carried out, for example, by refluxing a mixture of theproduct of step (iii) in excess triethylorthoformate for 24 hours. Theproduct precipitates on cooling.

Alternatively steps (ii), (iii) and (iv) may be telescoped by reactionof the product of step (i) with hydrazine hydrate under reflux in asolvent such as methanol, ethanol, acetonitrile or tetrahydrofuran,followed by refluxing a mixture of the precipitated product is excesstriethylorthoformate, as illustrated in Example 36 of WO 96/40681.

The invention will now be illustrated by the following non-limitingExamples in which, unless otherwise stated:

(i) yields are intended for the assistance of the reader only and arenot necessarily the maximum attainable by diligent process development;

(ii) ¹H NMR spectra were determined at 270MH₂ in CDCl₃ usingtetramethylsilane (TMS) as an internal standard, and are expressed aschemical shifts (delta values) in parts per million relative to TMSusing conventional abbreviations for designation of major peaks: s,singlet; m, multiplet; t, triplet; br, broad; d, doublet.

EXAMPLE 1

Step 1

Thionyl chloride (42 ml) was added dropwise over 60 minutes to water(250 ml) cooled to 0° C., maintaining the temperature of the mixturebetween 0-7° C. The solution was allowed to warm to 18° C. over 17hours. Copper(I) chloride (0.151 g) was added to the mixture and theresultant yellow-green solution was cooled to −3° C. using anice/acetone bath.

Step 2

36% w/w hydrochloric acid (135 ml) was added, with agitation, to3-amino-2-chloropyridine (17.3 g) maintaining the temperature of themixture below 30° C. with ice cooling. The reaction mixture was cooledto −5° C. using an ice/acetone bath and a solution of sodium nitrite(10.0 g) in water (40 ml) was added dropwise over 45 minutes,maintaining the temperature of the reaction mixture between −5 and 0° C.The resultant slurry was cooled to −2° C. and stirred for 10 minutes.

Step 3

The slurry from Step 2 was cooled to −5° C. and added to the solutionobtained from Step 1 over 95 minutes, maintaining the reactiontemperature between −3° to 0° C. (The slurry from Step 2 was maintainingat −5° C. throughout the addition). As the addition proceeded, a solidbegan to precipitate. When the addition was complete, the reactionmixture was agitated at 0° C. for 75 minutes. The suspended solid wascollected by vacuum filtration, washed with water (2×125 ml) and driedunder vacuum at below 35° C. to give 2-chloropyridine-3-sulfonylchloride (19.6 g; 70% yield); m.p. 42° C.; NMR: 7.50-7.60 (m, 1H),8.45-8.50 (m, 1H), 8.72-8.75 (m, 1H).

Alternatively the product was isolated by extraction of the coldreaction mixture with toluene (100 ml), washing with water (2×100 ml)and drying the toluene extract by azeotropic distillation at reducedpressure (300 mm Hg). The dried toluene solution of the product was thenused directly in a subsequent reaction.

EXAMPLE 2-10

Melting Point ¹H NMR Example Product Yield (° C.) (δ, ppm) 22-chloro-pyridine-5- 77 49-50 7.60(d, 1H) sulfonyl chloride 8.30(dd, 1H)9.03(d, 1H) 3 pyridine-3-sulfonyl 38 7.62(bt, 1H) chloride 8.20(d, 1H)8.21(bs, 1H) 9.30(bs, 1H) 4 4-chlorobenzene- 67 49-50 7.60(d, 2H)sulfonyl chloride 7.99(d, 2H) 5 4-cyanobenzene- 73 107-108 7.97(d, 2H)sulfonyl chloride 8.20(d, 2H) 6 3-nitrobenzene- 80 41-45 7.90(t, 1H)sulfonyl chloride 8.37-8.40(m, 1H) 8.60-8.62(m, 1H) 8.89-8.91(m, 1H) 74-nitrobenzene- 82 74-75 8.27(d, 2H) sulfonyl chloride 8.48(d, 2H) 84-(chlorosulfonyl)- 81 228-232 8.30(d, 2H) benzoic acid 8.40(d, 2H) 92-bromobenzene- 76 45-48 7.53-7.60(m, 2H) sulfonyl chloride 7.84-7.91(m,1H) 8.18-8.25(m, 1H) 10  3-chloro-4-cyano- 78 51-54 7.98-8.10(m, 2H)benzenesulfonyl 8.20(d, 1H) chloride

(1) 3-pyridinesulfonyl chloride is an oil which was soluble in thereaction mixture and was isolated by extraction into dichloromethane.

(2) In Examples 4-10 the amine hydrochlorides precipitated as solidsduring the addition of the amine to the aqueous hydrochloric acid. Toensure complete salt formation the mixture was heated at 30 to 50° C.for up to 60 minutes prior to cooling and addition of the aqueous sodiumnitrite solution.

(3) In Examples 4, 5 and 9, the products were obtained in two crops. Thesecond crop precipitated from the combined aqueous mother liquor andwash filtrates.

(4) In Examples 4, 8 and 9, the products precipitated from theirrespective reaction mixtures after allowing them to warm to 20° C. andstirring at that temperature for 65, 17 and 27 hours respectively.

(5) In Example 6, the product initially precipitated from the reactionmixture as an oil which crystallised during the agitation period priorto filtration.

(6) In Example 8, the NMR spectrum was determined in d₃-acetonitrile

(7) In Examples 2-10 the copper(I) chloride was dissolved in the waterprior to cooling and thionyl chloride addition

I claim:
 1. A process for the manufacture of a pyridinesulfonyl chlorideor a benzenesulfonyl chloride in which the benzene ring bears one ormore electron-withdrawing groups, comprising reacting a diazonium saltof an aminopyridine or aminobenzene in which the benzene ring bears oneor more electron withdrawing groups with a mixture of thionyl chloridein water, in the presence of an electron transfer catalyst.
 2. A processas claimed in claim 1 for the manufacture of a pyridinesulfonylchloride.
 3. A process as claimed in claim 1 for the manufacture of abenzenesulfonyl chloride in which the benzene ring bears one or moreelectron-withdrawing groups.
 4. A process as claimed in claim 1, whereinthe electron transfer catalyst is cupric chloride or cuprous chloride.5. A process as claimed in claim 2 for the manufacture of2-chloropyridine-3-sulfonyl chloride.
 6. A process as claimed in claim 3for the manufacture of a benzenesulfonyl chloride in which the benzenering bears 1 or 2 chloro, bromo, cyano, nitro or carboxy groups.
 7. Aprocess as claimed in claim 1 wherein the sulfonyl chloride is collectedby filtration from the reaction mixture.